Doxorubicin analogs incorporating chemically reactive substituents

Doxorubicin (1) analogues 2-5, incorporating the following alkylating or latent alkylating substituents, R, on the 3'-position of the daunosamine sugar have been synthesized as potential antitumor agents: 2, R = NHCOC6H4(p)SO2F; 3, R = NHCOCH2Br; 4, R = NHCOCH2Cl; 5, R = NHCON(NO)CH2CH2Cl. Thes...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1991-02, Vol.34 (2), p.561-564
Main Authors: Farquhar, David, Newman, Robert A, Zuckerman, Joan E, Andersson, Borje S
Format: Article
Language:English
Subjects:
Alicyclic compounds
Alicyclic compounds, terpenoids, prostaglandins, steroids
Animals
Antibiotics, Antineoplastic - chemical synthesis
Antibiotics, Antineoplastic - therapeutic use
Cell Line
Chemical Phenomena
Chemistry
Doxorubicin - analogs & derivatives
Exact sciences and technology
Humans
Leukemia L1210 - drug therapy
Leukemia P388 - drug therapy
Mice
Organic chemistry
Preparations and properties
Sarcoma, Experimental - drug therapy
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Summary:Doxorubicin (1) analogues 2-5, incorporating the following alkylating or latent alkylating substituents, R, on the 3'-position of the daunosamine sugar have been synthesized as potential antitumor agents: 2, R = NHCOC6H4(p)SO2F; 3, R = NHCOCH2Br; 4, R = NHCOCH2Cl; 5, R = NHCON(NO)CH2CH2Cl. These compounds were designed on the premise that alkylating anthracyclines might bind covalently to critical intracellular target macromolecules and overcome resistance to the parent agent attributable to reduced cellular drug accumulation. Growth inhibitory studies of the analogues were conducted in vitro against mouse leukemia cells (L1210 and P388) and human uterine sarcoma cells that are sensitive (MES-SA) and resistant (MES-SA/DOX) to doxorubicin. The analogues were 5-100-fold less potent than doxorubicin against the sensitive cell lines. However, they were only marginally cross-resistant with doxorubicin against MES-SA/DOX. Compounds 3 and 5 were also evaluated against a human myelocytic cell line (KBM-3) and a subline (KBM-3/DOX) resistant to doxorubicin. They were equally potent against both cell lines, indicating a complete lack of cross-resistance with doxorubicin. Alkylating anthracyclines may have potential for the treatment of tumors resistant to the parent agents.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00106a013